Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection

Kitazawa, Yusuke; Fujino, Masayuki; Sakai, Takatoshi; Azuma, Haruhito; Kimura, Hiromitsu; Isaka, Yoshitaka; Takahara, Shiro; Hünig, Thomas; Abe, Ryo; Li, Xiao-Kang

doi:10.1016/j.healun.2008.01.004

« Previous Next »The Journal of Heart and Lung Transplantation
Volume 27, Issue 4 , Pages 362-371, April 2008

Foxp3-expressing Regulatory T Cells Expanded With CD28 Superagonist Antibody Can Prevent Rat Cardiac Allograft Rejection

Yusuke Kitazawa, PhD
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
- Division of Immunology, Research Institute for Biological Science, Science University of Tokyo, Chiba, Japan.
Masayuki Fujino, PhD
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
Takatoshi Sakai, BS
- Shizuoka Laboratory Animal Center, Ltd., Shizuoka, Japan
Haruhito Azuma, MD, PhD
- Department of Urology, Osaka Medical College, Osaka, Japan
Hiromitsu Kimura, MD
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
Yoshitaka Isaka, MD, PhD
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan
Shiro Takahara, MD, PhD
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan
Thomas Hünig, MD, PhD
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
Ryo Abe, MD, PhD
- Division of Immunology, Research Institute for Biological Science, Science University of Tokyo, Chiba, Japan.
Xiao-Kang Li, MD, PhD
- Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
- Reprint requests: Xiao-Kang Li, MD, Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Telephone: +81-3-3416-0181. Fax: +81-3417-2816.

Background

It is well known that CD4⁺CD25⁺ regulatory T (Treg) cells play a central role in the suppression of autoimmunity, inflammation and allograft rejection. Therefore, therapeutic agents that capable of enhancing the number and activity of this T-cell subset are highly desirable.

Methods

The present study was designed to investigate the effects of superagonistic CD28-specific monoclonal antibody (supCD28 MAb) on preferentially expanded rat naturally occurring CD4⁺CD25⁺ Treg (nTreg) cells and its applicability in cardiac transplantation.

Results

A single administration of supCD28 MAb preferentially proliferated nTreg cells. The increase of Foxp3 expression and polarization toward a Th2 cytokine profile correlated with decreased production of interferon-γ and increased production of interleukin-4 and -10 in the expanded CD4⁺CD25⁺ Treg subset, which was capable of suppressing CD4⁺CD25⁻ T-cell proliferation after purification. Furthermore, supCD28 MAb administration revealed that nTreg cells were preferentially proliferating in vivo and recruited into the grafts, resulting in significant prolongation of full MHC-mismatch cardiac graft survival.

Conclusions

Our data demonstrate that supCD28 MAb targets expansion of nTreg cells in vivo and maintains and enhances their regulatory functions, which represents a major advance toward the therapeutic use of polyclonally activated Treg cells as cellular therapy for treatment of allograft rejection.